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Updated: May 28, 2026

Genome-wide RNAi Screening to Identify Host Factors That Modulate Oncolytic Virus Therapy
Published on: April 3, 2018
Reovirus therapy stimulates endoplasmic reticular stress, NOXA induction, and augments bortezomib-mediated apoptosis
K R Kelly1, C M Espitia, D Mahalingam
1Department of Medicine, The Institute for Drug Development, Cancer Therapy and Research Center, The University of Texas Health Science Center, San Antonio, TX 78229, USA.
Abstract:
Oncolytic virotherapy with reovirus has demonstrated anti-cancer activity and minimal toxicity in clinical trials, but the mechanisms underlying these effects have not been fully elucidated. Reolysin, a proprietary formulation of reovirus for cancer therapy, stimulated selective viral replication and apoptosis in multiple myeloma (MM) cells. Reolysin-mediated apoptosis was associated with an induction of endoplasmic reticular (ER) stress-related gene expression, swelling of the endoplasmic reticulum, increases in intracellular calcium levels and a strong induction of the Bcl-2 homology 3 (BH3)-only pro-apoptotic protein NOXA. Knockdown of NOXA expression by short hairpin RNA significantly reduced the pro-apoptotic effects of Reolysin. We next showed that co-administration of Reolysin and bortezomib resulted in the dual accumulation of viral and ubiquitinated proteins, which led to enhanced ER stress, NOXA induction and apoptosis. Importantly, the combination of reovirus infection and proteasomal inhibition significantly decreased tumor burden in a xenograft and syngeneic bone disease model of MM without exhibiting adverse side effects. Our study establishes ER stress stimulation and NOXA induction as novel mediators of reovirus-induced apoptosis. Furthermore, reovirus infection can be used as a promising approach to augment the anti-myeloma activity of bortezomib by promoting additional stress to the endoplasmic reticulum of MM cells.
Insights
Reolysin, a reovirus cancer therapy, induces apoptosis in multiple myeloma cells by triggering endoplasmic reticulum stress and NOXA protein. Combining Reolysin with bortezomib enhances anti-myeloma effects, reducing tumor burden with minimal side effects.
Area of Science:
- Oncolytic virotherapy
- Cancer biology
- Molecular oncology
Background:
- Reovirus demonstrates anti-cancer activity with low toxicity, but mechanisms remain unclear.
- Reolysin, a reovirus formulation, selectively replicates in and induces apoptosis in multiple myeloma (MM) cells.
Purpose of the Study:
- To elucidate the mechanisms of reovirus-mediated apoptosis in MM.
- To investigate the synergistic effects of Reolysin and bortezomib in MM treatment.
Main Methods:
- Assessed Reolysin's effect on MM cell apoptosis, ER stress markers, and NOXA protein.
- Utilized short hairpin RNA to knock down NOXA expression.
- Evaluated the combination of Reolysin and bortezomib in MM models.
Main Results:
- Reolysin induced MM cell apoptosis via ER stress and NOXA upregulation.
- NOXA knockdown diminished Reolysin's pro-apoptotic effects.
- Combination therapy enhanced ER stress, NOXA induction, and apoptosis, significantly reducing tumor burden in vivo.
- The combination therapy showed no adverse side effects.
Conclusions:
- ER stress and NOXA induction are novel mediators of reovirus-induced apoptosis.
- Reovirus infection potentiates bortezomib's anti-myeloma activity by increasing ER stress in MM cells.
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